WO2012090713A1 - Concomitant drug for improving cognitive function - Google Patents
Concomitant drug for improving cognitive function Download PDFInfo
- Publication number
- WO2012090713A1 WO2012090713A1 PCT/JP2011/078989 JP2011078989W WO2012090713A1 WO 2012090713 A1 WO2012090713 A1 WO 2012090713A1 JP 2011078989 W JP2011078989 W JP 2011078989W WO 2012090713 A1 WO2012090713 A1 WO 2012090713A1
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- Prior art keywords
- dementia
- popc
- dlpc
- cognitive function
- learning
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
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- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
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- A—HUMAN NECESSITIES
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- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
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- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Abstract
The purpose of the invention is to provide a drug and/or a food having an effect of improving cognitive function and a method for improving cognitive function.
The invention relates to a concomitant drug for improving cognitive function characterized by comprising 1,2-dilinoleoyl-sn-glycero-3-phosphocholine and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, the use of the concomitant drug for improving learning and/or memory, and a method for improving cognitive function and a method for improving a learning ability and/or a memorizing ability, each comprising administering the concomitant drug.
Description
本発明は、認知機能改善用併用剤、より詳細には認知機能改善のための２種類のホスファチジルコリンの併用に関する。
The present invention relates to a concomitant agent for improving cognitive function, and more particularly, to a combination of two types of phosphatidylcholines for improving cognitive function.
近年、認知症が世界的に医療上の大きな問題となっている。認知症は、記憶障害及び判断力の低下を中心にした多種の症状を伴う疾患であるが、その原因となる病気によって症状及びその経過は異なる。しかし、いずれの場合も、患者の生活の質を著しく損なうという点で共通している。また、患者の家族をはじめとする介護者にも多大な労苦を強いるという事実を考えたとき、認知症は社会的にたいへん重大な問題であるといえよう。寿命の長期化による高齢者人口の増加が、認知症患者の増加と関係しているため、日本では今後更に認知症患者が増加すると予測されている。また、認知症には分類されない何らかの認知障害を患う人も多い。
In recent years, dementia has become a major medical problem worldwide. Dementia is a disease with various symptoms centered on memory impairment and a decline in judgment, but the symptoms and their course differ depending on the disease that causes them. However, both cases are common in that the quality of life of the patient is significantly impaired. Dementia is also a serious social problem when considering the fact that it will cause a great deal of effort to caregivers including the patient's family. Since the increase in the elderly population due to prolonged lifespan is related to the increase in patients with dementia, it is predicted that the number of patients with dementia will increase in Japan in the future. Many people suffer from some cognitive impairment that is not classified as dementia.
認知症の原因となる病気は、現在までに多数挙げられているが、脳血管性認知症とアルツハイマー型認知症が最も多く、両者及びその複合型が、原因となる病気の大部分を占めている。特にアルツハイマー型認知症が、日本において近年増加している。
There are many illnesses that cause dementia, but cerebrovascular dementia and Alzheimer's dementia are the most common, and both and their combined forms account for the majority of the illnesses that cause it. Yes. In particular, Alzheimer-type dementia has increased in recent years in Japan.
認知症発症の詳細なメカニズムは未だ解明されていない。とはいえ、認知症患者において、様々な生化学的病変が報告されている。アルツハイマー型認知症及びレビー小体型認知症などにおいて報告されているのが、脳内のアセチルコリン濃度の低下である。この事実に基づき、認知症、特にアルツハイマー型認知症の治療において、アセチルコリン分解酵素阻害剤の使用が、現在までに最も成功している方法である。日本において既に市販されている塩酸ドネペジル（商品名アリセプト）をはじめ、多種のアセチルコリン分解酵素阻害剤がこれまで開発されている。しかし、それらの薬剤は、認知症を根本的に治療するものではなく、症状の進行を遅らせる効果を有するものである。また、塩酸ドネペジルに関して、急性腎不全及び横紋筋融解症などの発症の危険性が報告されているなど、副作用の問題もある。これらの理由から、より安全で効果の高い認知症改善薬の開発が待ち望まれており、その薬剤はアセチルコリン分解酵素阻害と異なる機序で作用するものである可能性が高い。
The detailed mechanism of the onset of dementia has not yet been elucidated. Nevertheless, various biochemical lesions have been reported in patients with dementia. What has been reported in Alzheimer type dementia and Lewy body type dementia is a decrease in the concentration of acetylcholine in the brain. Based on this fact, the use of acetylcholine degrading enzyme inhibitors is the most successful method to date in the treatment of dementia, particularly Alzheimer's dementia. Various acetylcholine degrading enzyme inhibitors have been developed so far, including donepezil hydrochloride (trade name: Aricept) already marketed in Japan. However, these drugs do not fundamentally treat dementia but have the effect of delaying the progression of symptoms. Further, regarding donepezil hydrochloride, there is a problem of side effects such as reports of the risk of developing acute renal failure and rhabdomyolysis. For these reasons, development of a safer and more effective dementia remedy has been awaited, and it is likely that the drug acts by a mechanism different from acetylcholine degrading enzyme inhibition.
本発明者は、塩酸ドネペジルとは異なる薬剤として、今までにホスファチジルコリンに認知機能改善作用があることを報告している（特許文献１）。しかしながら、依然として、認知機能を改善するための薬剤が求められているのが現状である。
The present inventor has reported that phosphatidylcholine has an effect of improving cognitive function as a drug different from donepezil hydrochloride (Patent Document 1). However, there is still a need for drugs for improving cognitive function.
本発明は、認知機能改善用薬剤及び認知機能を改善する方法を提供することを目的とする。
An object of the present invention is to provide a drug for improving cognitive function and a method for improving cognitive function.
本発明者は、以前の研究から、ホスファチジルコリンに認知機能改善作用があることを見出している。そこで、かかる知見に基づいて、より効果的に認知機能を改善し得る薬剤を得ることを目的としてさらに鋭意検討を重ねた。結果、特定の２種類のホスファチジルコリンの併用が、認知機能の改善に対してより効果的であることを見出し、さらに、臨床においても十分な効果を発揮することを確認して本発明を完成するに至った。即ち、本発明は、以下の通りである。
（１）１，２－ジリノレオイル－ｓｎ－グリセロ－３－ホスホコリン（ＤＬＰＣ）及び１－パルミトイル－２－オレオイル－ｓｎ－グリセロ－３－ホスホコリン（ＰＯＰＣ）を含有することを特徴とする、認知機能改善用併用剤。
（２）認知機能改善が、認知障害を伴う疾患又は状態を有する患者における認知機能改善である、上記（１）記載の併用剤。
（３）認知障害を伴う疾患又は状態が、認知症（老人性認知症、アルツハイマー型認知症、脳血管性認知症、外傷後認知症、脳腫瘍により生じる認知症、慢性硬膜下血腫により生じる認知症、正常圧脳水腫により生じる認知症、髄膜炎後認知症及びパーキンソン型認知症などの種々の疾患により生じる認知症）、非認知症性の認知障害（軽度認知障害（ＭＣＩ））、及び、学習又は記憶障害（脳発達障害に伴う学習及び記憶障害）からなる群から選択される少なくとも１種である、上記（２）記載の併用剤。
（４）学習能力及び／又は記憶能力の向上の為に使用されることを特徴とする、上記（１）記載の併用剤。
（５）食品である、上記（４）記載の併用剤。
（６）１，２－ジリノレオイル－ｓｎ－グリセロ－３－ホスホコリン（ＤＬＰＣ）の有効量及び１－パルミトイル－２－オレオイル－ｓｎ－グリセロ－３－ホスホコリン（ＰＯＰＣ）の有効量をそれを必要とする対象に投与することを含む、認知機能改善方法。
（７）認知機能改善が、認知障害を伴う疾患又は状態を有する患者における認知機能改善である、上記（６）記載の方法。
（８）認知障害を伴う疾患又は状態が、認知症（老人性認知症、アルツハイマー型認知症、脳血管性認知症、外傷後認知症、脳腫瘍により生じる認知症、慢性硬膜下血腫により生じる認知症、正常圧脳水腫により生じる認知症、髄膜炎後認知症及びパーキンソン型認知症などの種々の疾患により生じる認知症）、非認知症性の認知障害（軽度認知障害（ＭＣＩ））、及び、学習又は記憶障害（脳発達障害に伴う学習及び記憶障害）からなる群から選択される少なくとも１種である、上記（７）記載の方法。 The present inventor has found from a previous study that phosphatidylcholine has a cognitive function improving action. Based on this finding, further studies were conducted with the aim of obtaining a drug that can improve cognitive function more effectively. As a result, it was found that the combined use of two specific types of phosphatidylcholines is more effective for improving cognitive function, and further confirms that it exhibits a sufficient effect in clinical practice to complete the present invention. It came. That is, the present invention is as follows.
(1) Cognitive function characterized by containing 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) Concomitant drug for improvement.
(2) The combined agent according to (1) above, wherein the cognitive function improvement is cognitive function improvement in a patient having a disease or condition associated with cognitive impairment.
(3) The disease or condition associated with cognitive impairment is dementia (senile dementia, Alzheimer-type dementia, cerebrovascular dementia, post-traumatic dementia, dementia caused by brain tumor, cognition caused by chronic subdural hematoma Dementia caused by normal pressure cerebral edema, dementia caused by various diseases such as postmeningitis dementia and Parkinson's dementia), non-demented cognitive impairment (mild cognitive impairment (MCI)), and The combined use according to (2) above, which is at least one selected from the group consisting of learning or memory disorders (learning and memory disorders associated with brain development disorders).
(4) The combined use according to (1) above, which is used for improving learning ability and / or memory ability.
(5) The combination agent according to (4) above, which is a food.
(6) It requires an effective amount of 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC) and an effective amount of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) A method for improving cognitive function, comprising administering to a subject.
(7) The method according to (6), wherein the cognitive function improvement is cognitive function improvement in a patient having a disease or condition associated with cognitive impairment.
(8) The disease or condition associated with cognitive impairment is dementia (senile dementia, Alzheimer-type dementia, cerebrovascular dementia, post-traumatic dementia, dementia caused by brain tumor, cognition caused by chronic subdural hematoma Dementia caused by normal pressure cerebral edema, dementia caused by various diseases such as postmeningitis dementia and Parkinson's dementia), non-demented cognitive impairment (mild cognitive impairment (MCI)), and The method according to (7) above, which is at least one selected from the group consisting of learning or memory disorders (learning and memory disorders associated with brain development disorders).
（１）１，２－ジリノレオイル－ｓｎ－グリセロ－３－ホスホコリン（ＤＬＰＣ）及び１－パルミトイル－２－オレオイル－ｓｎ－グリセロ－３－ホスホコリン（ＰＯＰＣ）を含有することを特徴とする、認知機能改善用併用剤。
（２）認知機能改善が、認知障害を伴う疾患又は状態を有する患者における認知機能改善である、上記（１）記載の併用剤。
（３）認知障害を伴う疾患又は状態が、認知症（老人性認知症、アルツハイマー型認知症、脳血管性認知症、外傷後認知症、脳腫瘍により生じる認知症、慢性硬膜下血腫により生じる認知症、正常圧脳水腫により生じる認知症、髄膜炎後認知症及びパーキンソン型認知症などの種々の疾患により生じる認知症）、非認知症性の認知障害（軽度認知障害（ＭＣＩ））、及び、学習又は記憶障害（脳発達障害に伴う学習及び記憶障害）からなる群から選択される少なくとも１種である、上記（２）記載の併用剤。
（４）学習能力及び／又は記憶能力の向上の為に使用されることを特徴とする、上記（１）記載の併用剤。
（５）食品である、上記（４）記載の併用剤。
（６）１，２－ジリノレオイル－ｓｎ－グリセロ－３－ホスホコリン（ＤＬＰＣ）の有効量及び１－パルミトイル－２－オレオイル－ｓｎ－グリセロ－３－ホスホコリン（ＰＯＰＣ）の有効量をそれを必要とする対象に投与することを含む、認知機能改善方法。
（７）認知機能改善が、認知障害を伴う疾患又は状態を有する患者における認知機能改善である、上記（６）記載の方法。
（８）認知障害を伴う疾患又は状態が、認知症（老人性認知症、アルツハイマー型認知症、脳血管性認知症、外傷後認知症、脳腫瘍により生じる認知症、慢性硬膜下血腫により生じる認知症、正常圧脳水腫により生じる認知症、髄膜炎後認知症及びパーキンソン型認知症などの種々の疾患により生じる認知症）、非認知症性の認知障害（軽度認知障害（ＭＣＩ））、及び、学習又は記憶障害（脳発達障害に伴う学習及び記憶障害）からなる群から選択される少なくとも１種である、上記（７）記載の方法。 The present inventor has found from a previous study that phosphatidylcholine has a cognitive function improving action. Based on this finding, further studies were conducted with the aim of obtaining a drug that can improve cognitive function more effectively. As a result, it was found that the combined use of two specific types of phosphatidylcholines is more effective for improving cognitive function, and further confirms that it exhibits a sufficient effect in clinical practice to complete the present invention. It came. That is, the present invention is as follows.
(1) Cognitive function characterized by containing 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) Concomitant drug for improvement.
(2) The combined agent according to (1) above, wherein the cognitive function improvement is cognitive function improvement in a patient having a disease or condition associated with cognitive impairment.
(3) The disease or condition associated with cognitive impairment is dementia (senile dementia, Alzheimer-type dementia, cerebrovascular dementia, post-traumatic dementia, dementia caused by brain tumor, cognition caused by chronic subdural hematoma Dementia caused by normal pressure cerebral edema, dementia caused by various diseases such as postmeningitis dementia and Parkinson's dementia), non-demented cognitive impairment (mild cognitive impairment (MCI)), and The combined use according to (2) above, which is at least one selected from the group consisting of learning or memory disorders (learning and memory disorders associated with brain development disorders).
(4) The combined use according to (1) above, which is used for improving learning ability and / or memory ability.
(5) The combination agent according to (4) above, which is a food.
(6) It requires an effective amount of 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC) and an effective amount of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) A method for improving cognitive function, comprising administering to a subject.
(7) The method according to (6), wherein the cognitive function improvement is cognitive function improvement in a patient having a disease or condition associated with cognitive impairment.
(8) The disease or condition associated with cognitive impairment is dementia (senile dementia, Alzheimer-type dementia, cerebrovascular dementia, post-traumatic dementia, dementia caused by brain tumor, cognition caused by chronic subdural hematoma Dementia caused by normal pressure cerebral edema, dementia caused by various diseases such as postmeningitis dementia and Parkinson's dementia), non-demented cognitive impairment (mild cognitive impairment (MCI)), and The method according to (7) above, which is at least one selected from the group consisting of learning or memory disorders (learning and memory disorders associated with brain development disorders).
本発明の併用剤は、認知機能改善作用を有し、例えば、認知症、非認知症性の認知障害、及び学習又は記憶障害などを含む様々の疾患又は状態の予防又は治療、あるいは学習能力及び／又は記憶能力の向上に有用であり得る。
The concomitant drug of the present invention has an effect of improving cognitive function, for example, prevention or treatment of various diseases or conditions including dementia, non-demented cognitive impairment, and learning or memory impairment, or learning ability and It may be useful for improving memory capacity.
以下、本発明について詳細に説明する。
本発明は２種類の特定のホスファチジルコリンを併用することに特徴がある。
一方のホスファチジルコリンは、下記式 Hereinafter, the present invention will be described in detail.
The present invention is characterized in that two kinds of specific phosphatidylcholines are used in combination.
One phosphatidylcholine has the following formula:
本発明は２種類の特定のホスファチジルコリンを併用することに特徴がある。
一方のホスファチジルコリンは、下記式 Hereinafter, the present invention will be described in detail.
The present invention is characterized in that two kinds of specific phosphatidylcholines are used in combination.
One phosphatidylcholine has the following formula:
（式中、－Ｃ（Ｏ）Ｒ１及び－Ｃ（Ｏ）Ｒ２はそれぞれリノール酸残基である）で表される、ジリノレオイルホスファチジルコリン（１，２－ジリノレオイル－ｓｎ－グリセロ－３－ホスホコリン；以下、ＤＬＰＣ）である。
もう一方のホスファチジルコリンは、下記式 (Wherein —C (O) R 1 and —C (O) R 2 are each a linoleic acid residue), dilinoleoylphosphatidylcholine (1,2-dilinoleoyl-sn-glycero-3- Phosphocholine; hereinafter referred to as DLPC).
The other phosphatidylcholine has the following formula:
もう一方のホスファチジルコリンは、下記式 (Wherein —C (O) R 1 and —C (O) R 2 are each a linoleic acid residue), dilinoleoylphosphatidylcholine (1,2-dilinoleoyl-sn-glycero-3- Phosphocholine; hereinafter referred to as DLPC).
The other phosphatidylcholine has the following formula:
（式中、－Ｃ（Ｏ）Ｒ３はパルミチン酸残基であり、－Ｃ（Ｏ）Ｒ４はオレイン酸残基である）
で表される、パルミトイルオレオイルホスファチジルコリン（１－パルミトイル－２－オレオイル－ｓｎ－グリセロ－３－ホスホコリン；以下、ＰＯＰＣ）である。 (Wherein —C (O) R 3 is a palmitic acid residue and —C (O) R 4 is an oleic acid residue)
Palmitoyl oleoyl phosphatidylcholine (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine; hereinafter referred to as POPC) represented by
で表される、パルミトイルオレオイルホスファチジルコリン（１－パルミトイル－２－オレオイル－ｓｎ－グリセロ－３－ホスホコリン；以下、ＰＯＰＣ）である。 (Wherein —C (O) R 3 is a palmitic acid residue and —C (O) R 4 is an oleic acid residue)
Palmitoyl oleoyl phosphatidylcholine (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine; hereinafter referred to as POPC) represented by
ＤＬＰＣ及びＰＯＰＣは、その活性や安全性の面から誘導体化されていてもよい。例えば、水素添加、水酸化、アルキル化、ハロゲン化等の誘導体化が挙げられるが、これらに限定されない。
DLPC and POPC may be derivatized in view of their activity and safety. Examples thereof include, but are not limited to, derivatization such as hydrogenation, hydroxylation, alkylation, and halogenation.
本発明に用いるＤＬＰＣ及びＰＯＰＣは、動物（卵黄など）、植物（大豆など）、真菌（酵母、カビ）などから単離精製されたもの、化学的に合成されたもの等、特に制限はない。そして本発明に用いるＤＬＰＣ及びＰＯＰＣは、これを医薬として使用できる程度に精製されたものであれば、特に制限無く用いることができる。また、市販されているものを用いることもできる。
DLPC and POPC used in the present invention are not particularly limited, such as those isolated and purified from animals (eg, yolk), plants (eg, soybean), fungi (yeast, mold), and the like, and chemically synthesized. The DLPC and POPC used in the present invention can be used without particular limitation as long as they are purified to the extent that they can be used as pharmaceuticals. Moreover, what is marketed can also be used.
本発明において「併用剤」とは、上記ＤＬＰＣとＰＯＰＣとが併用されて投与されることを意味する。
In the present invention, the term “concomitant” means that the DLPC and POPC are administered in combination.
本発明の併用剤の投与形態は、特に限定されず、投与時に、ＤＬＰＣとＰＯＰＣとが組み合わされていればよい。このような投与形態としては、例えば、
（１）ＤＬＰＣとＰＯＰＣとを同時に製剤化して得られる単一の製剤としての投与、
（２）ＤＬＰＣとＰＯＰＣとを別々に製剤化して得られる２種の製剤の同一投与経路での同時投与、
（３）ＤＬＰＣとＰＯＰＣとを別々に製剤化して得られる２種の製剤の同一投与経路での時間差をおいての投与、
（４）ＤＬＰＣとＰＯＰＣとを別々に製剤化して得られる２種の製剤の異なる投与経路での同時投与、
（５）ＤＬＰＣとＰＯＰＣとを別々に製剤化して得られる２種の製剤の異なる投与経路での時間差をおいての投与
等が挙げられる。
簡便性の観点から、単一の製剤としての投与、又は２種の製剤の同一経路での同時投与が好ましい。 The administration form of the concomitant drug of the present invention is not particularly limited as long as DLPC and POPC are combined in administration. Examples of such dosage forms include:
(1) administration as a single preparation obtained by simultaneously formulating DLPC and POPC;
(2) Simultaneous administration by the same route of administration of two preparations obtained by separately formulating DLPC and POPC,
(3) Administration of two preparations obtained by separately formulating DLPC and POPC with a time difference in the same administration route,
(4) Simultaneous administration of two preparations obtained by separately formulating DLPC and POPC by different administration routes,
(5) Administration of two types of preparations obtained by separately formulating DLPC and POPC at different time intervals in different administration routes, and the like.
From the viewpoint of convenience, administration as a single preparation or simultaneous administration of two preparations by the same route is preferable.
（１）ＤＬＰＣとＰＯＰＣとを同時に製剤化して得られる単一の製剤としての投与、
（２）ＤＬＰＣとＰＯＰＣとを別々に製剤化して得られる２種の製剤の同一投与経路での同時投与、
（３）ＤＬＰＣとＰＯＰＣとを別々に製剤化して得られる２種の製剤の同一投与経路での時間差をおいての投与、
（４）ＤＬＰＣとＰＯＰＣとを別々に製剤化して得られる２種の製剤の異なる投与経路での同時投与、
（５）ＤＬＰＣとＰＯＰＣとを別々に製剤化して得られる２種の製剤の異なる投与経路での時間差をおいての投与
等が挙げられる。
簡便性の観点から、単一の製剤としての投与、又は２種の製剤の同一経路での同時投与が好ましい。 The administration form of the concomitant drug of the present invention is not particularly limited as long as DLPC and POPC are combined in administration. Examples of such dosage forms include:
(1) administration as a single preparation obtained by simultaneously formulating DLPC and POPC;
(2) Simultaneous administration by the same route of administration of two preparations obtained by separately formulating DLPC and POPC,
(3) Administration of two preparations obtained by separately formulating DLPC and POPC with a time difference in the same administration route,
(4) Simultaneous administration of two preparations obtained by separately formulating DLPC and POPC by different administration routes,
(5) Administration of two types of preparations obtained by separately formulating DLPC and POPC at different time intervals in different administration routes, and the like.
From the viewpoint of convenience, administration as a single preparation or simultaneous administration of two preparations by the same route is preferable.
以下、本発明において、「製剤」と称する場合は、ＤＬＰＣ及びＰＯＰＣとを同時に製剤化して得られる単一の製剤、及びＤＬＰＣとＰＯＰＣとを別々に製剤化して得られる２種の製剤の各々、のいずれをも包含する。
Hereinafter, in the present invention, when referred to as “formulation”, each of a single preparation obtained by simultaneously formulating DLPC and POPC, and two kinds of preparations obtained by separately formulating DLPC and POPC, Any of these are included.
本発明の併用剤におけるＤＬＰＣ及びＰＯＰＣの量は、それぞれ、該併用剤の投与形態（上述）、病気の重篤度、投与対象となる動物種、投与対象の薬物受容性、体重、年齢等によって異なる。通常、成人１日あたり、５０～５００ｍｇ、好ましくは１００～３００ｍｇのＤＬＰＣ、及び５０～５００ｍｇ、好ましくは１００～３００ｍｇのＰＯＰＣが対象に投与される。ＤＬＰＣとＰＯＰＣとの摂取比は１：１程度であることが好ましい。ＤＬＰＣ及びＰＯＰＣは併用することにより、それぞれを単独で用いた場合より、より少ない投与量とすることができる。
The amount of DLPC and POPC in the concomitant drug of the present invention depends on the administration form of the concomitant drug (described above), the severity of the disease, the species of animal to be administered, the drug acceptability of the administered object, body weight, age, etc. Different. Usually, 50-500 mg, preferably 100-300 mg of DLPC, and 50-500 mg, preferably 100-300 mg of POPC are administered to a subject per adult day. The intake ratio of DLPC to POPC is preferably about 1: 1. When DLPC and POPC are used in combination, the dose can be made smaller than when each of them is used alone.
本発明の併用剤は、有効成分であるＤＬＰＣ及びＰＯＰＣ以外に、任意の添加物、例えば医薬上許容され得る担体を含むことができる。医薬上許容され得る担体としては、例えば、ショ糖、デンプン、マンニット、ソルビット、乳糖、グルコース、セルロース、タルク、リン酸カルシウム、炭酸カルシウム等の賦形剤、セルロース、メチルセルロース、ヒドロキシプロピルセルロース、ポリプロピルピロリドン、ゼラチン、アラビアゴム、ポリエチレングリコール、ショ糖、デンプン等の結合剤、デンプン、カルボキシメチルセルロース、ヒドロキシプロピルスターチ、ナトリウム－グリコール－スターチ、炭酸水素ナトリウム、リン酸カルシウム、クエン酸カルシウム等の崩壊剤、ステアリン酸マグネシウム、エアロジル、タルク、ラウリル硫酸ナトリウム等の滑剤、クエン酸、メントール、グリシルリシン・アンモニウム塩、グリシン、オレンジ粉等の芳香剤、安息香酸ナトリウム、亜硫酸水素ナトリウム、メチルパラベン、プロピルパラベン等の保存剤、クエン酸、クエン酸ナトリウム、酢酸等の安定剤、メチルセルロース、ポリビニルピロリドン、ステアリン酸アルミニウム等の懸濁剤、界面活性剤等の分散剤、水、生理食塩水、オレンジジュース等の希釈剤、カカオ脂、ポリエチレングリコール、白灯油等のベースワックスなどが挙げられるが、それらに限定されない。
The concomitant agent of the present invention can contain any additive such as a pharmaceutically acceptable carrier in addition to the active ingredients DLPC and POPC. Examples of pharmaceutically acceptable carriers include sucrose, starch, mannitol, sorbit, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate, and other excipients, cellulose, methylcellulose, hydroxypropylcellulose, polypropylpyrrolidone. , Gelatin, gum arabic, polyethylene glycol, sucrose, starch and other binders, starch, carboxymethylcellulose, hydroxypropyl starch, sodium-glycol starch, sodium bicarbonate, calcium phosphate, calcium citrate and other disintegrants, magnesium stearate , Aerosil, Talc, Sodium lauryl sulfate lubricant, Citric acid, Menthol, Glycyllysine / Ammonium salt, Glycine, Orange powder, Fragrance, Sodium benzoate Preservatives such as lithium, sodium hydrogen sulfite, methyl paraben, propyl paraben, stabilizers such as citric acid, sodium citrate, acetic acid, suspensions such as methyl cellulose, polyvinyl pyrrolidone, aluminum stearate, dispersants such as surfactants, Examples include, but are not limited to, diluents such as water, physiological saline, and orange juice, base waxes such as cacao butter, polyethylene glycol, and white kerosene.
一つの実施態様において、本発明の併用剤は経口投与に好適な製剤として処方され得る。経口投与に好適な製剤は、水、生理食塩水のような希釈液に有効量の物質を溶解させた液剤、有効量の物質を固体や顆粒として含んでいるカプセル剤、顆粒剤、散剤又は錠剤、適当な分散媒中に有効量の物質を懸濁させた懸濁液剤、有効量の物質を溶解させた溶液を適当な分散媒中に分散させ乳化させた乳剤等である。
In one embodiment, the combination agent of the present invention can be formulated as a preparation suitable for oral administration. Preparations suitable for oral administration include solutions in which an effective amount of a substance is dissolved in a diluent such as water or physiological saline, capsules, granules, powders or tablets containing the effective amount of the substance as solids or granules. A suspension in which an effective amount of a substance is suspended in an appropriate dispersion medium, an emulsion in which a solution in which an effective amount of a substance is dissolved is dispersed in an appropriate dispersion medium, and the like.
別の実施態様において、本発明の併用剤は非経口的な投与に好適な製剤として処方され得る。非経口的な投与（例、静脈内注射、皮下注射、筋肉注射、局所注入など）に好適な製剤としては、水性および非水性の等張無菌の注射液剤があり、これには抗酸化剤、緩衝液、制菌剤、等張化剤等が含まれていてもよい。また、水性および非水性の無菌の懸濁液剤が挙げられ、これには懸濁剤、可溶化剤、増粘剤、安定化剤、防腐剤等が含まれていてもよい。当該製剤は、アンプルやバイアルのように単位投与量あるいは複数回投与量ずつ容器に封入することができる。また、有効成分および医薬上許容され得る担体を凍結乾燥し、使用直前に適当な無菌のビヒクルに溶解又は懸濁すればよい状態で保存することもできる。
In another embodiment, the combination of the present invention can be formulated as a preparation suitable for parenteral administration. Formulations suitable for parenteral administration (eg, intravenous injection, subcutaneous injection, intramuscular injection, local infusion, etc.) include aqueous and non-aqueous isotonic sterile injection solutions, which include antioxidants, Buffers, antibacterial agents, isotonic agents and the like may be included. Aqueous and non-aqueous sterile suspensions are also included, which may contain suspending agents, solubilizers, thickeners, stabilizers, preservatives and the like. The preparation can be enclosed in a container in unit doses or multiple doses like ampoules and vials. In addition, the active ingredient and a pharmaceutically acceptable carrier can be lyophilized and stored in a state that may be dissolved or suspended in a suitable sterile vehicle immediately before use.
有効成分としてＤＬＰＣ及びＰＯＰＣを含有する本発明の併用剤は、哺乳動物（例、マウス、ラット、ハムスター、ウサギ、ネコ、イヌ、ウシ、ヒツジ、サル、ヒトなど）に対して認知機能を改善する作用を有し、従ってＤＬＰＣ及びＰＯＰＣを含有する本発明の併用剤は、認知障害を伴う疾患又は状態の予防又は治療用として有用であり、医薬品として提供される。認知障害を伴う疾患又は状態としては、具体的には、認知症（例、老人性認知症、アルツハイマー型認知症、脳血管性認知症、外傷後認知症、脳腫瘍により生じる認知症、慢性硬膜下血腫により生じる認知症、正常圧脳水腫により生じる認知症、髄膜炎後認知症及びパーキンソン型認知症などの種々の疾患により生じる認知症）、非認知症性の認知障害（例、軽度認知障害（ＭＣＩ））、学習又は記憶障害（例、脳発達障害に伴う学習及び記憶障害）などを含む様々の疾患又は状態が挙げられる。さらに本発明の併用剤は、学習や記憶（例、短期記憶、長期記憶）の向上のために使用することができる。
The combination agent of the present invention containing DLPC and POPC as active ingredients improves cognitive function for mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human, etc.). The combined agent of the present invention having an action and thus containing DLPC and POPC is useful for the prevention or treatment of a disease or condition associated with cognitive impairment, and is provided as a pharmaceutical product. The disease or condition associated with cognitive impairment specifically includes dementia (eg, senile dementia, Alzheimer's dementia, cerebrovascular dementia, post-traumatic dementia, dementia caused by brain tumor, chronic dura mater Dementia caused by hematoma, dementia caused by normal pressure cerebral edema, dementia caused by various diseases such as postmeningitis dementia and Parkinsonian dementia, non-demented cognitive impairment (eg, mild cognition) Disorders (MCI)), learning or memory disorders (eg, learning and memory disorders associated with brain development disorders) and the like. Furthermore, the concomitant drug of the present invention can be used for improving learning and memory (eg, short-term memory, long-term memory).
本明細書中で用いられる場合、「予防」とは、認知障害、学習・記憶障害等を示さない対象（被験体）において、該症状が顕在化するのを防ぐことを意味し、「治療」とは、認知障害、学習・記憶障害等を示す被験体において、該症状を軽減すること、あるいは該症状の悪化を防ぐこと又は遅延させることを意味する。「改善」とは、認知障害、学習・記憶障害等を示さない対象においては、認知能力や学習・記憶能力の向上を意味し、認知障害、学習・記憶障害等を示す被験体においては、該症状を緩和、好ましくは日常生活に差し支えない程度にまで症状を緩和することを意味する。
As used herein, “prevention” means preventing the manifestation of the symptom in a subject (subject) that does not exhibit cognitive impairment, learning / memory impairment, etc., and “treatment” In the subject exhibiting cognitive impairment, learning / memory impairment, etc., it means that the symptom is reduced, or worsening of the symptom is prevented or delayed. “Improvement” means an improvement in cognitive ability or learning / memory ability in subjects who do not show cognitive impairment, learning / memory impairment, etc. It means alleviating symptoms, preferably to such an extent that they do not interfere with daily life.
本発明の併用剤は、食品として提供することができる。有効成分としてＤＬＰＣ及びＰＯＰＣを含有する本発明の併用剤は、哺乳動物（例、マウス、ラット、ハムスター、ウサギ、ネコ、イヌ、ウシ、ヒツジ、サル、ヒトなど）に対して認知機能を改善する作用を有し、従って有効成分としてＤＬＰＣ及びＰＯＰＣを含有する本発明の併用剤は、認知障害を伴う疾患や状態の予防や調節に効果的である。特に認知障害を伴う疾患や状態の予防や調節に効果的な機能性食品、及び学習や記憶の向上に効果的な機能性食品として提供することができる。
The combination agent of the present invention can be provided as food. The combination agent of the present invention containing DLPC and POPC as active ingredients improves cognitive function for mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human, etc.). The combination agent of the present invention having an action and thus containing DLPC and POPC as active ingredients is effective for the prevention and regulation of diseases and conditions associated with cognitive impairment. In particular, it can be provided as a functional food effective in preventing or regulating diseases and conditions associated with cognitive impairment, and a functional food effective in improving learning and memory.
本発明において「食品」とは、医薬品及び医薬部外品以外の全ての飲食物を意味する。例えば、特定保健用食品、栄養機能食品、及びいわゆるサプリメントを含むが、これらに限定されない。
In the present invention, “food” means all foods and drinks other than drugs and quasi drugs. Examples include, but are not limited to, foods for specified health use, nutritional functional foods, and so-called supplements.
本発明の併用剤を食品として用いる場合には、食品としては、例えば、一般食品（例えば、パン、乳製品（例、牛乳、ヨーグルト）、菓子、キャンデー、飴、チョコレート、ケーキ、プリン、ゼリー、清涼飲料水、麺類）、健康食品、ダイエタリーサプリメント、並びに厚生労働省の保健機能食品制度に規定される特定保健用食品及び栄養機能食品が挙げられる。該食品は、液状物（水溶性、不溶性）、粉末、顆粒、錠剤、カプセル等の固形物、ゼリー状等の半固形物などの任意の形態であり得る。本発明の併用剤は水又は所定の水溶液に溶解して用いることができる。このような場合、本発明の併用剤は溶解補助物（例、リノール酸）、安定化剤を含んでいてもよい。
When the concomitant agent of the present invention is used as a food, examples of the food include general foods (for example, bread, dairy products (eg, milk, yogurt), confectionery, candy, rice cake, chocolate, cake, pudding, jelly, Soft drinks, noodles), health foods, dietary supplements, and foods for specified health use and nutritional function foods as defined in the Health Function Food System of the Ministry of Health, Labor and Welfare. The food may be in any form such as a liquid (water-soluble or insoluble), a solid such as a powder, a granule, a tablet or a capsule, or a semi-solid such as a jelly. The concomitant agent of the present invention can be used by dissolving in water or a predetermined aqueous solution. In such a case, the combination agent of the present invention may contain a solubilizer (eg, linoleic acid) and a stabilizer.
本発明の併用剤を食品として用いる場合、その摂取量は、用いる形態（例、液状物、固形物、半固形物）、ＤＬＰＣ及びＰＯＰＣの含有濃度、並びにＤＬＰＣ及びＰＯＰＣ以外に含まれる成分の有無、種類及び量等によって異なり一概に云えないが、通常、食品中に、ＤＬＰＣ及びＰＯＰＣの合計量が好ましくは３０％以上、より好ましくは９０％以上の割合で含められる。食品中のＤＬＰＣ及びＰＯＰＣ以外の成分としては、上記した任意の添加物が挙げられる。
When the concomitant drug of the present invention is used as a food, the amount of intake is the form used (eg, liquid, solid, semi-solid), DLPC and POPC concentration, and presence or absence of components other than DLPC and POPC. However, the total amount of DLPC and POPC is usually included in the food in a proportion of preferably 30% or more, and more preferably 90% or more. As ingredients other than DLPC and POPC in food, the above-mentioned arbitrary additives can be mentioned.
本発明の併用剤は、該併用剤の単位摂取量又はその分割量が個別に包装又は充填されたもの、あるいは多数の単位摂取量又はその分割量が包括的に包装又は充填されたものであり得る。
本発明の併用剤が、単一の製剤として提供される場合には、該併用剤の単位摂取量又はその分割量は、ＤＬＰＣ及びＰＯＰＣ両方の、即ち、ホスファチジルコリン全体の単位摂取量又はその分割量である。本発明の併用剤が、２種の製剤の併用として提供される場合には、該併用剤の単位摂取量又はその分割量は、ＤＬＰＣの単位摂取量又は分割量と、ＰＯＰＣの単位摂取量又はその分割量との組み合わせである。 The concomitant drug of the present invention is one in which the unit intake of the concomitant drug or a divided amount thereof is individually packaged or filled, or a plurality of unit intakes or divided amounts thereof are comprehensively packaged or filled. obtain.
When the concomitant drug of the present invention is provided as a single preparation, the unit intake of the concomitant drug or a divided amount thereof is the unit intake of both DLPC and POPC, that is, the total phosphatidylcholine or the divided amount thereof. It is. When the concomitant drug of the present invention is provided as a combination of two kinds of preparations, the unit intake of the concomitant drug or the divided amount thereof includes DLPC unit intake or divided amount and POPC unit intake or It is a combination with the division amount.
本発明の併用剤が、単一の製剤として提供される場合には、該併用剤の単位摂取量又はその分割量は、ＤＬＰＣ及びＰＯＰＣ両方の、即ち、ホスファチジルコリン全体の単位摂取量又はその分割量である。本発明の併用剤が、２種の製剤の併用として提供される場合には、該併用剤の単位摂取量又はその分割量は、ＤＬＰＣの単位摂取量又は分割量と、ＰＯＰＣの単位摂取量又はその分割量との組み合わせである。 The concomitant drug of the present invention is one in which the unit intake of the concomitant drug or a divided amount thereof is individually packaged or filled, or a plurality of unit intakes or divided amounts thereof are comprehensively packaged or filled. obtain.
When the concomitant drug of the present invention is provided as a single preparation, the unit intake of the concomitant drug or a divided amount thereof is the unit intake of both DLPC and POPC, that is, the total phosphatidylcholine or the divided amount thereof. It is. When the concomitant drug of the present invention is provided as a combination of two kinds of preparations, the unit intake of the concomitant drug or the divided amount thereof includes DLPC unit intake or divided amount and POPC unit intake or It is a combination with the division amount.
単位摂取量又はその分割量が個別に包装又は充填された医薬品あるいは食品としては、例えば、単位摂取量又はその分割量を、通常の包装物（例えば、ＰＴＰ（press through packing）シート、紙容器、フィルム（例、プラスチックフィルム）容器、ガラス容器、プラスチック容器）中に別々に包装又は充填したものが挙げられる。このように個別に包装又は充填された医薬品あるいは食品は、さらに組み合わされて、１つの容器（例えば、紙容器、フィルム（例、プラスチックフィルム）容器、ガラス容器、プラスチック容器）中に一緒に包装又は充填されていてもよい。多数の単位摂取量又はその分割量が包括的に包装又は充填された医薬品あるいは食品としては、例えば、多数の錠剤又はカプセル剤が区分されることなく１つの容器（例えば、紙容器、フィルム（例、プラスチックフィルム）容器、ガラス容器、プラスチック容器）中に包装又は充填されたものが挙げられる。本発明の医薬品あるいは食品はまた、単位摂取量又はその分割量を、長期間の摂取に十分な数で含み得るが、例えば食品の場合であれば３日以上、好ましくは７日、１０日、１４日又は２１日以上あるいは１ヶ月、２ヶ月、３ヶ月以上の摂取に十分な数で含み得る。
As a medicine or food in which the unit intake or its divided amount is individually packaged or filled, for example, the unit intake or its divided amount is converted into a normal package (for example, a PTP (press through packing) sheet, a paper container, What was wrapped or filled separately in a film (for example, plastic film) container, a glass container, a plastic container) is mentioned. Such individually packaged or filled pharmaceuticals or foods can be further combined and packaged together in one container (eg, paper container, film (eg, plastic film) container, glass container, plastic container). It may be filled. As a pharmaceutical or food in which a large number of unit intakes or divided amounts thereof are comprehensively packaged or filled, for example, a single container (eg, paper container, film (eg, , Plastic film) containers, glass containers, plastic containers) or the like packed or filled. The pharmaceutical product or food of the present invention may also contain a unit intake or a divided amount thereof in a sufficient number for long-term intake. For example, in the case of food, 3 days or more, preferably 7 days, 10 days, It may be included in numbers sufficient for ingestion for 14 days or 21 days or more, 1 month, 2 months, 3 months or more.
本発明の併用剤には、必須の有効成分であるＤＬＰＣ及びＰＯＰＣに加え、他の、神経変性疾患を予防又は治療し得る１種類以上の化合物を含めてもよい。
In addition to DLPC and POPC, which are essential active ingredients, one or more compounds that can prevent or treat neurodegenerative diseases may be included in the concomitant drug of the present invention.
他の神経変性疾患を予防又は治療する化合物の例として、ポリフェノール、コエンザイムＱ１０、β－シトステロール、イソフラボン、メビニン酸、ビタミンＣ、ビタミンＥ、フラボノイド類、テルペン類、葉酸、ビタミンＢ６、ビタミンＢ１２、セスキルペンラクトン、ウロキナーゼ、ナットウキナーゼ、ジリノレオイルホスファチジルエタノールアミン、硫化プロピル、リンゴペクチン、酢酸、ＥＰＡ、及びＤＨＡが挙げられる。
Examples of compounds that prevent or treat other neurodegenerative diseases include polyphenols, coenzyme Q10, β-sitosterol, isoflavones, mevinic acid, vitamin C, vitamin E, flavonoids, terpenes, folic acid, vitamin B6, vitamin B12, ce Skill pen lactone, urokinase, nattokinase, dilinoleoylphosphatidylethanolamine, propyl sulfide, apple pectin, acetic acid, EPA, and DHA.
本発明において、ＤＬＰＣ及びＰＯＰＣを併用投与することにより、哺乳動物（例、マウス、ラット、ハムスター、ウサギ、ネコ、イヌ、ウシ、ヒツジ、サル、ヒトなど）に対して認知機能を改善し得る。従ってＤＬＰＣ及びＰＯＰＣを併用投与することにより、認知障害を伴う疾患又は状態の予防又は治療が可能となる。認知障害を伴う疾患又は状態としては、具体的には、認知症（例、老人性認知症、アルツハイマー型認知症、脳血管性認知症、外傷後認知症、脳腫瘍により生じる認知症、慢性硬膜下血腫により生じる認知症、正常圧脳水腫により生じる認知症、髄膜炎後認知症及びパーキンソン型認知症などの種々の疾患により生じる認知症）、非認知症性の認知障害（例、軽度認知障害（ＭＣＩ））、学習又は記憶障害（例、脳発達障害に伴う学習及び記憶障害）などを含む様々の疾患又は状態が挙げられる。さらに本発明のＤＬＰＣ及びＰＯＰＣを併用投与することにより、学習や記憶（例、短期記憶、長期記憶）の向上が期待できる。本発明の方法におけるＤＬＰＣ及びＰＯＰＣの投与量や投与形態は、上記本発明の併用剤で述べたものと同様である。
In the present invention, cognitive function can be improved for mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human, etc.) by administering DLPC and POPC together. Therefore, by jointly administering DLPC and POPC, it becomes possible to prevent or treat a disease or condition associated with cognitive impairment. The disease or condition associated with cognitive impairment specifically includes dementia (eg, senile dementia, Alzheimer's dementia, cerebrovascular dementia, post-traumatic dementia, dementia caused by brain tumor, chronic dura mater Dementia caused by hematoma, dementia caused by normal pressure cerebral edema, dementia caused by various diseases such as postmeningitis dementia and Parkinsonian dementia, non-demented cognitive impairment (eg, mild cognition) Disorders (MCI)), learning or memory disorders (eg, learning and memory disorders associated with brain development disorders) and the like. Furthermore, improvement of learning and memory (eg, short-term memory, long-term memory) can be expected by administering DLPC and POPC of the present invention in combination. The dosage and dosage form of DLPC and POPC in the method of the present invention are the same as those described in the above-mentioned combination agent of the present invention.
本明細書中で挙げられた特許及び特許出願明細書を含む全ての刊行物に記載された内容は、本明細書での引用により、その全てが明示されたと同程度に本明細書に組み込まれるものである。
The contents of all publications, including patents and patent application specifications cited in this specification, are hereby incorporated by reference herein to the same extent as if all were explicitly stated. Is.
以下に実施例を挙げ、本発明を更に詳しく説明するが、本発明は下記実施例等に何ら制限されるものではない。
Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to the following examples.
（実験方法及び材料）
１．水迷路試験
雄性ウィスターラット（７週）を水迷路試験に用いた。円形のプラスチック製の水槽（直径１８０ｃｍ、深さ４５ｃｍ）を用いた。水槽の内側は全て黒色に塗り、底から２５ｃｍまで墨汁で濁った水を満たした（２２℃）。黒色に塗ったプラットホーム（直径１１ｃｍ）を水中に置き、水面下１ｃｍ水没するようにした。水槽は試験室に置き、ラットが水槽から見られる目印を幾つか設けた。試験を行っている間は、目印の位置は変えずにおいた。プラットホームを水槽の中央と端から等距離のところにある一定の位置、すなわち、４分円の一つの中心に設けた。無作為に選択した５箇所のうちの一つに水槽の壁に向き合わせてラットを放し、プラットホーム上に退避するまでの時間（習得潜時：acquisition latency）を測定した。うまく退避できれば、ラットをそのままプラットホーム上で１０秒間滞在させた。水迷路試験の７日前から試験の間中、毎日、ポリエチレングリコール（ＰＥＧ）に溶解したＤＬＰＣ（５ｍｇ／ｋｇ）単独、ＤＬＰＣ（１０ｍｇ／ｋｇ）単独、ＰＯＰＣ（５ｍｇ／ｋｇ）単独、ＰＯＰＣ（１０ｍｇ／ｋｇ）単独、又はＤＬＰＣ（５ｍｇ／ｋｇ）及びＰＯＰＣ（５ｍｇ／ｋｇ）、あるいはＰＥＧ単独を経口投与した。水迷路試験は、１日に２回試験を行い、２回目の試験は最初の試験の２分後に開始した。連続して８日間試験を行い、連続した２日間からプラットホームにたどりつくまでの習得潜時の平均値（±ＳＥＭ）を計算した。 (Experimental methods and materials)
1. Water maze test Male Wistar rats (7 weeks) were used in the water maze test. A circular plastic water tank (diameter 180 cm, depth 45 cm) was used. The inside of the aquarium was all painted black and filled with muddy water from the bottom up to 25 cm (22 ° C.). A platform (diameter 11 cm) painted in black was placed in water and submerged 1 cm below the surface of the water. The water tank was placed in the test room, and some marks were provided so that rats could be seen from the water tank. During the test, the place of the mark was left unchanged. The platform was set at a certain position equidistant from the center and end of the water tank, that is, at one center of the quadrant. The rat was released from one of five randomly selected locations facing the aquarium wall, and the time taken to retreat onto the platform (acquisition latency) was measured. If the evacuation was successful, the rat was allowed to stay on the platform for 10 seconds. DLPC (5 mg / kg) alone, DLPC (10 mg / kg) alone, POPC (5 mg / kg) alone, POPC (10 mg / kg) dissolved in polyethylene glycol (PEG) every day from 7 days before the water maze test. kg) alone, or DLPC (5 mg / kg) and POPC (5 mg / kg), or PEG alone was orally administered. The water maze test was tested twice a day and the second test started 2 minutes after the first test. The test was conducted continuously for 8 days, and the average value (± SEM) of the learning latency from the continuous 2 days until reaching the platform was calculated.
１．水迷路試験
雄性ウィスターラット（７週）を水迷路試験に用いた。円形のプラスチック製の水槽（直径１８０ｃｍ、深さ４５ｃｍ）を用いた。水槽の内側は全て黒色に塗り、底から２５ｃｍまで墨汁で濁った水を満たした（２２℃）。黒色に塗ったプラットホーム（直径１１ｃｍ）を水中に置き、水面下１ｃｍ水没するようにした。水槽は試験室に置き、ラットが水槽から見られる目印を幾つか設けた。試験を行っている間は、目印の位置は変えずにおいた。プラットホームを水槽の中央と端から等距離のところにある一定の位置、すなわち、４分円の一つの中心に設けた。無作為に選択した５箇所のうちの一つに水槽の壁に向き合わせてラットを放し、プラットホーム上に退避するまでの時間（習得潜時：acquisition latency）を測定した。うまく退避できれば、ラットをそのままプラットホーム上で１０秒間滞在させた。水迷路試験の７日前から試験の間中、毎日、ポリエチレングリコール（ＰＥＧ）に溶解したＤＬＰＣ（５ｍｇ／ｋｇ）単独、ＤＬＰＣ（１０ｍｇ／ｋｇ）単独、ＰＯＰＣ（５ｍｇ／ｋｇ）単独、ＰＯＰＣ（１０ｍｇ／ｋｇ）単独、又はＤＬＰＣ（５ｍｇ／ｋｇ）及びＰＯＰＣ（５ｍｇ／ｋｇ）、あるいはＰＥＧ単独を経口投与した。水迷路試験は、１日に２回試験を行い、２回目の試験は最初の試験の２分後に開始した。連続して８日間試験を行い、連続した２日間からプラットホームにたどりつくまでの習得潜時の平均値（±ＳＥＭ）を計算した。 (Experimental methods and materials)
1. Water maze test Male Wistar rats (7 weeks) were used in the water maze test. A circular plastic water tank (diameter 180 cm, depth 45 cm) was used. The inside of the aquarium was all painted black and filled with muddy water from the bottom up to 25 cm (22 ° C.). A platform (diameter 11 cm) painted in black was placed in water and submerged 1 cm below the surface of the water. The water tank was placed in the test room, and some marks were provided so that rats could be seen from the water tank. During the test, the place of the mark was left unchanged. The platform was set at a certain position equidistant from the center and end of the water tank, that is, at one center of the quadrant. The rat was released from one of five randomly selected locations facing the aquarium wall, and the time taken to retreat onto the platform (acquisition latency) was measured. If the evacuation was successful, the rat was allowed to stay on the platform for 10 seconds. DLPC (5 mg / kg) alone, DLPC (10 mg / kg) alone, POPC (5 mg / kg) alone, POPC (10 mg / kg) dissolved in polyethylene glycol (PEG) every day from 7 days before the water maze test. kg) alone, or DLPC (5 mg / kg) and POPC (5 mg / kg), or PEG alone was orally administered. The water maze test was tested twice a day and the second test started 2 minutes after the first test. The test was conducted continuously for 8 days, and the average value (± SEM) of the learning latency from the continuous 2 days until reaching the platform was calculated.
２．ミニメンタルステート（Mini Mental State Examination（ＭＭＳＥ））テスト
ＭＭＳＥテストを、認知障害を有する、５９歳～９５歳（平均、７６±１．１歳）の患者３１０人（男性１３５人、女性１７５人）について行なった。２１４人の患者にはＰＯＰＣ（９０ｍｇ／ｄａｙ）を、２１人にはＤＬＰＣ（１００ｍｇ／ｄａｙ）を、７５人にはＤＬＰＣ（５０ｍｇ／ｄａｙ）とＰＯＰＣ（４５ｍｇ／ｄａｙ）とを、それぞれ朝食後に１回、経口的に投与した。ＭＭＳＥテストについては、満点を３０とし、２０未満の場合を軽度認知障害及び認知症と判定した。 2. Mini Mental State Examination (MMSE) test The MMSE test was performed on 310 patients (135 men, 175 women) aged 59 to 95 years (average, 76 ± 1.1 years) with cognitive impairment. Was done. 214 patients received POPC (90 mg / day), 21 patients received DLPC (100 mg / day), 75 patients received DLPC (50 mg / day) and POPC (45 mg / day) after breakfast. Administered orally. For the MMSE test, the perfect score was 30, and the case of less than 20 was determined as mild cognitive impairment and dementia.
ＭＭＳＥテストを、認知障害を有する、５９歳～９５歳（平均、７６±１．１歳）の患者３１０人（男性１３５人、女性１７５人）について行なった。２１４人の患者にはＰＯＰＣ（９０ｍｇ／ｄａｙ）を、２１人にはＤＬＰＣ（１００ｍｇ／ｄａｙ）を、７５人にはＤＬＰＣ（５０ｍｇ／ｄａｙ）とＰＯＰＣ（４５ｍｇ／ｄａｙ）とを、それぞれ朝食後に１回、経口的に投与した。ＭＭＳＥテストについては、満点を３０とし、２０未満の場合を軽度認知障害及び認知症と判定した。 2. Mini Mental State Examination (MMSE) test The MMSE test was performed on 310 patients (135 men, 175 women) aged 59 to 95 years (average, 76 ± 1.1 years) with cognitive impairment. Was done. 214 patients received POPC (90 mg / day), 21 patients received DLPC (100 mg / day), 75 patients received DLPC (50 mg / day) and POPC (45 mg / day) after breakfast. Administered orally. For the MMSE test, the perfect score was 30, and the case of less than 20 was determined as mild cognitive impairment and dementia.
（結果）
実験例１．ラットにおける習得潜時に対する、ＤＬＰＣ単独投与、ＰＯＰＣ単独投与、及びＤＬＰＣとＰＯＰＣの併用投与の効果
ラットにＰＥＧ、ＤＬＰＣ（５ｍｇ／ｋｇ）、ＤＬＰＣ（１０ｍｇ／ｋｇ）、ＰＯＰＣ（５ｍｇ／ｋｇ）、ＰＯＰＣ（１０ｍｇ／ｋｇ）又は、ＤＬＰＣ（５ｍｇ／ｋｇ）及びＰＯＰＣ（５ｍｇ／ｋｇ）を試験７日前から水迷路試験の間中毎日経口投与した。
ＤＬＰＣ（５ｍｇ／ｋｇ）及びＰＯＰＣ（５ｍｇ／ｋｇ）を併用した場合に、ラットの習得潜時は顕著に短縮化した。一方、ＤＬＰＣ（５ｍｇ／ｋｇ、１０ｍｇ／ｋｇ）単独投与あるいはＰＯＰＣ（５ｍｇ／ｋｇ、１０ｍｇ／ｋｇ）単独投与の場合には、顕著な効果は観察されなかった（図１）。
このことは、ＤＬＰＣとＰＯＰＣの併用が学習及び記憶能力を増強し得ることを示唆している。 (result)
Experimental Example 1 Effects of DLPC single administration, POPC single administration, and combined administration of DLPC and POPC on acquisition latency in rats PEG, DLPC (5 mg / kg), DLPC (10 mg / kg), POPC (5 mg / kg), POPC in rats (10 mg / kg) or DLPC (5 mg / kg) and POPC (5 mg / kg) were orally administered daily throughout the water maze test from 7 days before the test.
When DLPC (5 mg / kg) and POPC (5 mg / kg) were used in combination, the learning latency of rats was significantly shortened. On the other hand, when DLPC (5 mg / kg, 10 mg / kg) alone or POPC (5 mg / kg, 10 mg / kg) alone was administered, no significant effect was observed (FIG. 1).
This suggests that the combined use of DLPC and POPC can enhance learning and memory ability.
実験例１．ラットにおける習得潜時に対する、ＤＬＰＣ単独投与、ＰＯＰＣ単独投与、及びＤＬＰＣとＰＯＰＣの併用投与の効果
ラットにＰＥＧ、ＤＬＰＣ（５ｍｇ／ｋｇ）、ＤＬＰＣ（１０ｍｇ／ｋｇ）、ＰＯＰＣ（５ｍｇ／ｋｇ）、ＰＯＰＣ（１０ｍｇ／ｋｇ）又は、ＤＬＰＣ（５ｍｇ／ｋｇ）及びＰＯＰＣ（５ｍｇ／ｋｇ）を試験７日前から水迷路試験の間中毎日経口投与した。
ＤＬＰＣ（５ｍｇ／ｋｇ）及びＰＯＰＣ（５ｍｇ／ｋｇ）を併用した場合に、ラットの習得潜時は顕著に短縮化した。一方、ＤＬＰＣ（５ｍｇ／ｋｇ、１０ｍｇ／ｋｇ）単独投与あるいはＰＯＰＣ（５ｍｇ／ｋｇ、１０ｍｇ／ｋｇ）単独投与の場合には、顕著な効果は観察されなかった（図１）。
このことは、ＤＬＰＣとＰＯＰＣの併用が学習及び記憶能力を増強し得ることを示唆している。 (result)
Experimental Example 1 Effects of DLPC single administration, POPC single administration, and combined administration of DLPC and POPC on acquisition latency in rats PEG, DLPC (5 mg / kg), DLPC (10 mg / kg), POPC (5 mg / kg), POPC in rats (10 mg / kg) or DLPC (5 mg / kg) and POPC (5 mg / kg) were orally administered daily throughout the water maze test from 7 days before the test.
When DLPC (5 mg / kg) and POPC (5 mg / kg) were used in combination, the learning latency of rats was significantly shortened. On the other hand, when DLPC (5 mg / kg, 10 mg / kg) alone or POPC (5 mg / kg, 10 mg / kg) alone was administered, no significant effect was observed (FIG. 1).
This suggests that the combined use of DLPC and POPC can enhance learning and memory ability.
実験例２．認知障害におけるＰＯＰＣ及びＤＬＰＣ併用投与の効果
認知障害におけるＰＯＰＣ及びＤＬＰＣの併用投与の効果をＭＭＳＥテストにより調べた。
７５人の患者に対して、朝食後に１回、ＰＯＰＣ（５０ｍｇ／ｄａｙ）及びＤＬＰＣ（４５ｍｇ／ｄａｙ）を経口的に摂取させた後で、ＭＭＳＥテストを月１回の割合で実施した。結果を図２に示す。
また、同様にして、ＰＯＰＣ単独（９０ｍｇ/ｄａｙ、朝食後１回、毎日）を経口的に摂取させた２１４人の患者、ＤＬＰＣ単独（１００ｍｇ／ｄａｙ、朝食後１回、毎日）を経口的に摂取させた２１人の患者についても、ＭＭＳＥテストを月１回の割合で実施した。摂取前と摂取して５カ月後でのＭＭＳＥスコアの差を算出した（Δ increase in MMSE score)。結果を図３に示す。
本試験で調べた患者（３１０人）のうち凡そ６５％が軽度認知障害及び認知症を患っている。ＰＯＰＣとＤＬＰＣとの両方を摂取した７５患者について、摂取前の平均ＭＭＳＥスコアは１４．７±０．７であった（図２）。朝食後１回、毎日ＤＬＰＣ（５０ｍｇ／ｄａｙ）とＰＯＰＣ（４５ｍｇ／ｄａｙ）とを併用摂取すると、顕著にＭＭＳＥスコアが上昇し、平均スコアは２０を超えた。すなわち、摂取後５カ月では正常な認知機能にまで回復した（図２）。
ＤＬＰＣ（５０ｍｇ／ｄａｙ）とＰＯＰＣ（４５ｍｇ／ｄａｙ）とを併用摂取して５カ月の患者では、ＰＯＰＣ（９０ｍｇ／ｄａｙ）を単独摂取した患者、あるいはＤＬＰＣ（１００ｍｇ／ｄａｙ）を単独摂取した患者に比べて、より顕著にＭＭＳＥスコアが上昇した（図３）。
これらの結果は、ＤＬＰＣとＰＯＰＣとの併用処置がＰＯＰＣやＤＬＰＣをそれぞれ単独で処置した場合に比べてより軽度認知障害や認知症を改善するのに効果的であることを示している。 Experimental Example 2. Effect of combined administration of POPC and DLPC on cognitive impairment The effect of combined administration of POPC and DLPC on cognitive impairment was examined by MMSE test.
75 patients received POPC (50 mg / day) and DLPC (45 mg / day) orally once after breakfast, followed by a monthly MMSE test. The results are shown in FIG.
Similarly, 214 patients who were orally ingested POPC alone (90 mg / day, once daily after breakfast) orally, DLPC alone (100 mg / day, once daily after breakfast, daily) The MMSE test was also conducted once a month for the 21 patients ingested. The difference in MMSE score before and after intake was calculated (Δ increase in MMSE score). The results are shown in FIG.
Approximately 65% of patients (310) examined in this study suffer from mild cognitive impairment and dementia. For 75 patients who took both POPC and DLPC, the mean MMSE score before consumption was 14.7 ± 0.7 (FIG. 2). When DLPC (50 mg / day) and POPC (45 mg / day) were taken together once daily after breakfast, the MMSE score markedly increased and the average score exceeded 20. That is, it recovered to normalcognitive function 5 months after ingestion (FIG. 2).
For patients who have taken DLPC (50 mg / day) and POPC (45 mg / day) in combination for 5 months, patients who took POPC (90 mg / day) alone, or patients who took DLPC (100 mg / day) alone In comparison, the MMSE score increased more significantly (FIG. 3).
These results indicate that the combined treatment of DLPC and POPC is more effective in improving mild cognitive impairment and dementia compared to the case where POPC and DLPC are each treated alone.
認知障害におけるＰＯＰＣ及びＤＬＰＣの併用投与の効果をＭＭＳＥテストにより調べた。
７５人の患者に対して、朝食後に１回、ＰＯＰＣ（５０ｍｇ／ｄａｙ）及びＤＬＰＣ（４５ｍｇ／ｄａｙ）を経口的に摂取させた後で、ＭＭＳＥテストを月１回の割合で実施した。結果を図２に示す。
また、同様にして、ＰＯＰＣ単独（９０ｍｇ/ｄａｙ、朝食後１回、毎日）を経口的に摂取させた２１４人の患者、ＤＬＰＣ単独（１００ｍｇ／ｄａｙ、朝食後１回、毎日）を経口的に摂取させた２１人の患者についても、ＭＭＳＥテストを月１回の割合で実施した。摂取前と摂取して５カ月後でのＭＭＳＥスコアの差を算出した（Δ increase in MMSE score)。結果を図３に示す。
本試験で調べた患者（３１０人）のうち凡そ６５％が軽度認知障害及び認知症を患っている。ＰＯＰＣとＤＬＰＣとの両方を摂取した７５患者について、摂取前の平均ＭＭＳＥスコアは１４．７±０．７であった（図２）。朝食後１回、毎日ＤＬＰＣ（５０ｍｇ／ｄａｙ）とＰＯＰＣ（４５ｍｇ／ｄａｙ）とを併用摂取すると、顕著にＭＭＳＥスコアが上昇し、平均スコアは２０を超えた。すなわち、摂取後５カ月では正常な認知機能にまで回復した（図２）。
ＤＬＰＣ（５０ｍｇ／ｄａｙ）とＰＯＰＣ（４５ｍｇ／ｄａｙ）とを併用摂取して５カ月の患者では、ＰＯＰＣ（９０ｍｇ／ｄａｙ）を単独摂取した患者、あるいはＤＬＰＣ（１００ｍｇ／ｄａｙ）を単独摂取した患者に比べて、より顕著にＭＭＳＥスコアが上昇した（図３）。
これらの結果は、ＤＬＰＣとＰＯＰＣとの併用処置がＰＯＰＣやＤＬＰＣをそれぞれ単独で処置した場合に比べてより軽度認知障害や認知症を改善するのに効果的であることを示している。 Experimental Example 2. Effect of combined administration of POPC and DLPC on cognitive impairment The effect of combined administration of POPC and DLPC on cognitive impairment was examined by MMSE test.
75 patients received POPC (50 mg / day) and DLPC (45 mg / day) orally once after breakfast, followed by a monthly MMSE test. The results are shown in FIG.
Similarly, 214 patients who were orally ingested POPC alone (90 mg / day, once daily after breakfast) orally, DLPC alone (100 mg / day, once daily after breakfast, daily) The MMSE test was also conducted once a month for the 21 patients ingested. The difference in MMSE score before and after intake was calculated (Δ increase in MMSE score). The results are shown in FIG.
Approximately 65% of patients (310) examined in this study suffer from mild cognitive impairment and dementia. For 75 patients who took both POPC and DLPC, the mean MMSE score before consumption was 14.7 ± 0.7 (FIG. 2). When DLPC (50 mg / day) and POPC (45 mg / day) were taken together once daily after breakfast, the MMSE score markedly increased and the average score exceeded 20. That is, it recovered to normal
For patients who have taken DLPC (50 mg / day) and POPC (45 mg / day) in combination for 5 months, patients who took POPC (90 mg / day) alone, or patients who took DLPC (100 mg / day) alone In comparison, the MMSE score increased more significantly (FIG. 3).
These results indicate that the combined treatment of DLPC and POPC is more effective in improving mild cognitive impairment and dementia compared to the case where POPC and DLPC are each treated alone.
本発明の併用剤は、認知機能改善作用を有し、例えば、認知症、非認知症性の認知障害、及び学習又は記憶障害などを含む様々の疾患又は状態の予防又は治療、あるいは学習能力及び／又は記憶能力の向上に有用であり得る。
The concomitant drug of the present invention has an effect of improving cognitive function, for example, prevention or treatment of various diseases or conditions including dementia, non-demented cognitive impairment, and learning or memory impairment, or learning ability and It may be useful for improving memory capacity.
本出願は日本で出願された特願２０１０－２９４４８７（出願日：平成２２年１２月２９日）を基礎としており、その内容は本明細書にすべて包含される。
This application is based on Japanese Patent Application No. 2010-294487 filed in Japan (filing date: December 29, 2010), the contents of which are incorporated in full herein.
Claims (8)
- １，２－ジリノレオイル－ｓｎ－グリセロ－３－ホスホコリン及び１－パルミトイル－２－オレオイル－ｓｎ－グリセロ－３－ホスホコリンを含有することを特徴とする、認知機能改善用併用剤。 A cognitive function-improving concomitant drug containing 1,2-dilinoleoyl-sn-glycero-3-phosphocholine and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine.
- 認知機能改善が、認知障害を伴う疾患又は状態を有する患者における認知機能改善である、請求項１記載の併用剤。 The co-administration agent according to claim 1, wherein the cognitive function improvement is a cognitive function improvement in a patient having a disease or condition associated with cognitive impairment.
- 認知障害を伴う疾患又は状態が、認知症、非認知症性の認知障害、及び、学習又は記憶障害からなる群から選択される少なくとも１種である、請求項２記載の併用剤。 The combination drug according to claim 2, wherein the disease or condition associated with cognitive impairment is at least one selected from the group consisting of dementia, non-demented cognitive impairment, and learning or memory impairment.
- 学習能力及び／又は記憶能力の向上の為に使用されることを特徴とする、請求項１記載の併用剤。 The combination agent according to claim 1, which is used for improving learning ability and / or memory ability.
- 食品である、請求項４記載の併用剤。 The combination agent according to claim 4, which is a food.
- １，２－ジリノレオイル－ｓｎ－グリセロ－３－ホスホコリン（ＤＬＰＣ）の有効量及び１－パルミトイル－２－オレオイル－ｓｎ－グリセロ－３－ホスホコリン（ＰＯＰＣ）の有効量をそれを必要とする対象に投与することを含む、認知機能改善方法。 An effective amount of 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC) and an effective amount of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) for subjects in need thereof A method for improving cognitive function, comprising administering.
- 認知機能改善が、認知障害を伴う疾患又は状態を有する患者における認知機能改善である、請求項６記載の方法。 The method according to claim 6, wherein the cognitive function improvement is a cognitive function improvement in a patient having a disease or condition associated with cognitive impairment.
- 認知障害を伴う疾患又は状態が、認知症、非認知症性の認知障害、及び、学習又は記憶障害からなる群から選択される少なくとも１種である、請求項７記載の方法。 The method according to claim 7, wherein the disease or condition associated with cognitive impairment is at least one selected from the group consisting of dementia, non-demented cognitive impairment, and learning or memory impairment.
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| JP2012550820A JP5896474B2 (en) | 2010-12-29 | 2011-12-15 | Concomitant drugs for improving cognitive function |
| EP11853728.1A EP2659892B1 (en) | 2010-12-29 | 2011-12-15 | Concomitant drug for improving cognitive function |
| KR1020137017972A KR101522123B1 (en) | 2010-12-29 | 2011-12-15 | Concomitant drug for improving cognitive function |
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| WO2015056675A1 (en) * | 2013-10-15 | 2015-04-23 | 株式会社西崎創薬研究所 | Antidepressant combination drug |
| CN105682481A (en) * | 2013-10-21 | 2016-06-15 | 酶学技术有限公司 | Compositions comprising choline and derivatives thereof, uses thereof and processes for their preparation |
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| WO2020264324A1 (en) * | 2019-06-26 | 2020-12-30 | Kannalife Sciences, Inc. | Use of certain phosphatidylcholines containing long chain polyunsaturated fatty acids as neuroprotective agents |
| AU2021293331A1 (en) * | 2020-06-18 | 2023-02-02 | Morinaga Milk Industry Co., Ltd. | Cognitive function improving agent, cognitive function maintaining agent, hippocampus function improving agent, and hippocampus function maintaining agent |
| CN113509474A (en) * | 2021-08-31 | 2021-10-19 | 广东工业大学 | Application of beta-sitosterol in preparation of anti-neuritis medicine |
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| IL84840A0 (en) | 1987-12-16 | 1988-06-30 | Rapaport Erich | Dietary supplement |
| JP3073224B2 (en) | 1990-08-08 | 2000-08-07 | キユーピー株式会社 | Food or pharmaceutical composition for improving brain function and method for producing the same |
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| XIA,H. ET AL.: "Analysis of soybean phosphatidylcholine molecular species using high performance liquid chromatography", FENXI SHIYANSHI, vol. 22, no. 1, 2003, pages 9 - 11, XP008168813 * |
| YOKO MATSUMOTO ET AL.: "Comparative examination of the effects of egg yolk and soybean phosphatidylcholine on memories of the low memory mice", THE JAPANESE SOCIETY OF NUTRITION AND FOOD SCIENCE SOKAI KOEN YOSHISHU, vol. 50TH, 1996, pages 244, XP008168960 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015056675A1 (en) * | 2013-10-15 | 2015-04-23 | 株式会社西崎創薬研究所 | Antidepressant combination drug |
| JPWO2015056675A1 (en) * | 2013-10-15 | 2017-03-09 | 株式会社 西崎創薬研究所 | Antidepressant combination |
| US9655911B2 (en) * | 2013-10-15 | 2017-05-23 | Nishizaki Bioinformation Research Institute | Antidepressant combination drug |
| CN105682481A (en) * | 2013-10-21 | 2016-06-15 | 酶学技术有限公司 | Compositions comprising choline and derivatives thereof, uses thereof and processes for their preparation |
Also Published As
| Publication number | Publication date |
|---|---|
| JP5896474B2 (en) | 2016-03-30 |
| KR101522123B1 (en) | 2015-05-20 |
| JPWO2012090713A1 (en) | 2014-06-05 |
| EP2659892B1 (en) | 2018-05-23 |
| CN103402524B (en) | 2015-09-02 |
| US20130274228A1 (en) | 2013-10-17 |
| EP2659892A1 (en) | 2013-11-06 |
| EP2659892A4 (en) | 2015-04-29 |
| CN103402524A (en) | 2013-11-20 |
| KR20130102633A (en) | 2013-09-17 |
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